Micheliolide derivatives, medicinal composition, producing method and usage thereof

ABSTRACT

The present invention provides a compound of formula (I)

CROSS-REFERENCE TO RELATED APPLICATION

The application is a continuation in part of PCT/CN2011/072782 (filed onApr. 14, 2011), which claims priority of Chinese patent application201010153701.0 (filed on Apr. 23, 2010) and priority of Chinese patentapplication 201010510726.1 (filed on Oct. 18, 2010), the contents ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical technology, and morespecifically, relates to micheliolide derivatives or salt thereof, andpharmaceutical composition using which as the effective ingredient forthe cancer treatment or auxiliary swelling treatment, producing methodsthereof, and the usage of the compound and composition in producinganti-cancer or auxiliary anti-cancer drugs.

BACKGROUND OF THE INVENTION

Tumor threats the human health seriously. There are about 200 millioncancer patients in China and the number is added by 1.6 million peryear, which is a big group. The anti-cancer research is a challengingand significant field in life science and technology. At present, thecommonly used clinical anti-cancer drugs are cytotoxic drugs. Thecharacteristics of these drugs are poor selectivity, strong sideeffects, drug resistance and so on. They are a typical double-edgedsword drugs, and difficult to eradicate cancer, which result in highproportion of cancer recurrence. The high rate of the recurrence ofcancer has troubled the doctors, and more and more studies confirm thatthere are a few tumor stem cells in the tumor cell population which canamplify the cell groups. Tumor stem cells are usually in a slow cyclestatus and have low sensitivity to chemotherapeutic drugs. They are thesource of tumor recurrence. The found of the tumor stem cell makes a newtarget for cancer treatment, and the drug research focused on the tumorstem cell may be able to cure cancer completely.

In recent years, investigations on anti-cancer compounds from naturalproducts have become the hotspot of anti-cancer drug development. Forthe past 20 years, 61% new small molecule entities drugs may be derivedfrom natural products. Natural products are very common in sometherapeutic areas: 78% of the antibacterial compounds and 74% ofanti-tumor compounds are natural products or derived from naturalproducts. Practice has proved that the unique role of natural productsin anticancer drug discovery re-attach great attention. The traditionaltreatment of cancer chemotherapy drug have resistance problem,especially the low sensitivity to tumor stem cells. Traditional Chinesemedicine (TCM) is profound in anti-cancer field, high efficiency and lowtoxicity. Accordingly, there is high chance to find drugs eradicatingcancer stem cells for cure of malignant tumor from TCM.

Parthenolide, a sesquiterpene lactone extracted from TanacetumParthenium, was originally used to treat skin infections, rheumatism,and migraine. Recent studies have shown that parthenolide can inhibitthe growth of cancer cells, such as prostate cancer, breast cancer,gastric cancer, leukemia, kidney cancer, lung cancer, colonadenocarcinoma, and medulloblastoma. Furthermore, parthenolide iseffective on treatment of UV-induced skin cancer in animal model. Thestudy of its mechanism finds that parthenolide can inhibit theactivation of the transcription factor NF-κB. The activity was mainlyderived from the thiol on the subunit of p65/NF-κB which conductsMichael addition reaction with parthenolide. NF-κB is a key gene toregulate tumor invasion, metastasis, and drug resistance genes;therefore, inhibition of NF-κB activation may increase the sensitivityof tumor apoptosis to tumor inhibitor. Recently, Ph.D. Jordan, C. T. andhis colleagues found that parthenolide can selectively eliminate cancerstem cells without damage of normal stem cells, which make it possibleto suppress recurrence AML. This unique mechanism action of parthenolidehas attracted widespread attention.

Micheliolide belongs to guaiane-type sesquiterpene lacones. It has beenreported in the literature [J. Nat. Prod. 1993, 56, 90-98; Bioorg. Med.Chem. Lett. 2003, 11, 1503-1510]. On the basis of the results, thepresent invention reports the use of micheliolide derivatives and itssalts in the cancer treatment.

SUMMARY OF THE INVENTION

The embodiments of present invention provides micheliolide derivative,an anti-cancer pharmaceutical composition comprising an effective amountof micheliolide derivative formula (I) or their salts, methods ofpreparing them, and the use of micheliolide derivative formula (I) ortheir salts, or their pharmaceutical composition for preparinganticancer drugs.

To achieve the above-mentioned objectives, technical scheme providedincludes:

A compound or salt thereof of formula (I) is provided,

Wherein:

R₁ is H, —C(O)R₄ or —C(O)R₅R₆, where R₅ and R₆ are the same ordifferent, R₄, R₅ and R₆ are hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, aryl, alkyaryl, arylakyl, arylalkenyl, arylalkynyl andheterocyclic;

R₂═R₃ is double bond, or

R₃ is hydrogen, R₂ is alkyl having in the range of 1 up to 8 carbonatoms containing substitute, where the substituent is selected formcycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino acid fragment, or—NR₇R₈, and its pharmaceutically acceptable salts formed with inorganicand/or organic acid and its quaternary ammonium salts formed with R₉Z.Preferred substituents are amino acid fragment and methylene substitutedby —NR₇R₈,

where R₇ and R₈ are the same or different, they are hydrogen, alkyl,cycloalkyl, alkyl substituted by hydroxyl, alkenyl, alkynyl, aryl,alkyaryl, arylakyl, arylalkenyl, arylalkynyl, heterocyclic,trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, cabamate,sulfonyl, sulfonamide or aryloxyalkyl; or R₇ and R₈ together with N forma ring, the ring number is preferable 3-9, the ring can have one or moresubstituents on it, substituents are selected from hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl, arylalkenyl,arylalkynyl and heterocyclic, R₇ and R₈ are preferably selected fromhydrogen, alkyl having in the range of 1 up to 8 carbon atoms, orcycloalkyl;

Z is fluorine, chlorine, bromine, iodine, tosylate, methanesulfonate,benzenesulfonate, trifluoromethanesulfonate, R9 is alkyl, cycloalkyl,alkyl substituted by hydroxyl, alkenyl, alkynyl, aryl, heterocyclic,arylakyl, arylalkenyl, arylalkynyl, cyanomethyl, alkoxy or aryloxyalkyl;inorganic or organic acid are hydrofluoric acid, hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoricacid, carbonic acid, boric acid, selenious acid, phosphomolybdic acid,phosphorous acid, sulfurous acid, citric acid, maleic acid, D-malicacid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid,DL-lactic acid, oxalic acid, methanesulfonic acid, valeric acid, oleicacid, lauric acid, para-toluenesulfonic acid, 1-naphthalensulfonic acid,2-naphthalensulfonic acid, phthalic acid, tartaric acid, malonic acid,succinic acid, fumaric acid, glycolic acid, thioglycolic acid, glycine,sarcocine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinicacid, benzoic acid and substituted benzoic acid;

X is O or R₁₀N, R₁₀ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, alkyaryl, arylakyl, arylalkenyl, arylalkynyl or heterocyclic;

Y is single bond, O, R₁₁N, R₁₂R₁₃C, R₁₁ is hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, alkyaryl, arylakyl, arylalkenyl, arylalkynyl orheterocyclic; R₁₂ and R₁₃ are the same or different, they are hydrogen,fluorine, chlorine, bromine, iodine, alkyl, cycloalkyl, alkylsubstituted by hydroxyl, alkenyl, alkynyl, aryl, heterocyclic, arylakyl,arylalkenyl, arylalkynyl, cyanomethyl, alkoxy or aryloxyalkyl.

Herein, R₁ being H, Y being single bond in not compatible with R₂═R₃being double bond.

Preferably, R₂ is methylene substituted by —NR₇R₈ or amino acidfragment, where R₇ and R₈ are the same or different, they are hydrogen,alkyl, cycloalkyl, alkyl substituted by hydroxyl, alkenyl, alkynyl,aryl, alkyaryl, arylakyl, arylalkenyl, arylalkynyl, heterocyclic,trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, cabamate,sulfonyl, sulfonamide or aryloxyalkyl; or R₇ and R₈ together with N forma ring, the ring number is preferable 3-9, the ring can have one or moresubstituents on it, substituents are selected from hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl, arylalkenyl,arylalkynyl and heterocyclic, R₇ and R₈ are preferably selected fromhydrogen, alkyl having in the range of 1 up to 8 carbon atoms, orcycloalkyl.

The invention also provide a method of producing a compound or saltthereof of formula (I), including: considering micheliolide as material,adding catalyst into organic solvent, and reacting the organic solventwith the catalyst and the material having the corresponding group orstructure to obtain the target compound.

Preferably, a compound or salt thereof of formula (I) is represented byformula (II), formula (III), formula (IV), or formula (V)

Specifically, the invention provides a method of producing micheliolidederivative of formula (II), comprising: reacting materials to obtain thetarget compound, wherein the materials are micheliolide anddimethylamine.

Specifically, the invention provides a method of producing a compound offormula (III), comprising: reacting materials, solvent and catalyst toobtain the target compound, wherein, the materials are micheliolide andpropionylchloride, the catalyst is triethylamine, and the solvent isCH₂Cl₂.

Specifically, the invention provides a method of producing a compound offormula (IV), comprising: reacting materials and solvent to obtain thetarget compound, wherein, the materials are micheliolide and3-chloroperbenzoic acid, the solvent is CH₂Cl₂.

Specifically, the invention provides a method of producing a compound offormula (V), comprising: dissolving material in CH₂Cl₂, wherein thematerial is a compound of formula (V);

adjusting the pH to 4-5 by using of hydrochloric acid;

lyophilizing the aqueous solution to obtain the target compound.

The invention also provides a usage of the compound or salt thereof offormula (I) for curing a cancer, wherein, the cancer includes leukemia,breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectalcancer, lung cancer, liver cancer, esophageal carcinoma, gastric cancer,intestinal cancer, renal carcinoma, oral cavity cancer, Hochkinlymphoma, pancreas cancer, colorectal cancer, cervical cancer, NonHochkin lymphoma, giiomas, melanoma, bladder carcinoma, ovarian cancer,thyroid carcinoma, Card Posey meat cancer.

The invention also provides a usage of the compound or salt thereof offormula (I) for cancer auxiliary treatment, wherein, the cancer includesleukemia, breast cancer, Prostate cancer, nasopharyngeal carcinoma,colorectal cancer, lung cancer, liver cancer, esophageal carcinoma,gastric cancer, intestinal cancer, renal carcinoma, oral cavity cancer,Hochkin lymphoma, pancreas cancer, colorectal cancer, cervical cancer,Non Hochkin lymphoma, giiomas, melanoma, bladder carcinoma, ovariancancer, thyroid carcinoma, Card Posey meat cancer.

The invention also provides a usage of the compound or salt thereof offormula (I) in a drug, wherein, the drug is used for cancer medicaltreatment, and the cancer includes leukemia, breast cancer, Prostatecancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, livercancer, esophageal carcinoma, gastric cancer, intestinal cancer, renalcarcinoma, oral cavity cancer, Hochkin lymphoma, pancreas cancer,colorectal cancer, cervical cancer, Non Hochkin lymphoma, giiomas,melanoma, bladder carcinoma, ovarian cancer, thyroid carcinoma, CardPosey meat cancer.

The invention also provides a usage of the compound or salt thereof offormula (I) in a drug, wherein, the drug is used for cancer auxiliarymedical treatment, and the cancer includes leukemia, breast cancer,Prostate cancer, nasopharyngeal carcinoma, colorectal cancer, lungcancer, liver cancer, esophageal carcinoma, gastric cancer, intestinalcancer, renal carcinoma, oral cavity cancer, Hochkin lymphoma, pancreascancer, colorectal cancer, cervical cancer, Non Hochkin lymphoma,giiomas, melanoma, bladder carcinoma, ovarian cancer, thyroid carcinoma,Card Posey meat cancer.

The invention also provides a pharmaceutical composition for cancertreatment, comprising an effective amount of micheliolide derivatives orsalt thereof of formula (I), in combination with a pharmaceuticallyacceptable carrier or other anti-cancer drug.

The invention also provides usage of the compound or salt thereof offormula (II), (III), (IV), (V) for curing a cancer, wherein, the cancerincludes to leukemia, breast cancer, Prostate cancer, nasopharyngealcarcinoma, colorectal cancer, lung cancer, liver cancer, esophagealcarcinoma, gastric cancer, intestinal cancer, renal carcinoma, oralcavity cancer, Hochkin lymphoma, pancreas cancer, colorectal cancer,cervical cancer, Non Hochkin lymphoma, giiomas, melanoma, bladdercarcinoma, ovarian cancer, thyroid carcinoma, Card Posey meat cancer.

The invention also provides usage of the compound or salt thereof offormula (II), (III), (IV), (V) for cancer auxiliary treatment, wherein,the cancer includes leukemia, breast cancer, Prostate cancer,nasopharyngeal carcinoma, colorectal cancer, lung cancer, liver cancer,esophageal carcinoma, gastric cancer, intestinal cancer, renalcarcinoma, oral cavity cancer, Hochkin lymphoma, pancreas cancer,colorectal cancer, cervical cancer, Non Hochkin lymphoma, giiomas,melanoma, bladder carcinoma, ovarian cancer, thyroid carcinoma, CardPosey meat cancer.

The invention also provides usage of the compound or salt thereof offormula (II), (III), (W), (V) in a drug, wherein, the drug is used forcancer medical treatment, and the cancer includes leukemia, breastcancer, Prostate cancer, nasopharyngeal carcinoma, colorectal cancer,lung cancer, liver cancer, esophageal carcinoma, gastric cancer,intestinal cancer, renal carcinoma, oral cavity cancer, Hochkinlymphoma, pancreas cancer, colorectal cancer, cervical cancer, NonHochkin lymphoma, giiomas, melanoma, bladder carcinoma, ovarian cancer,thyroid carcinoma, Card Posey meat cancer.

The invention also provides usage of the compound or salt thereof offormula (II), (III), (W), (V) in a drug, wherein, the drug is used forcancer auxiliary medical treatment, and the cancer includes leukemia,breast cancer, Prostate cancer, nasopharyngeal carcinoma, colorectalcancer, lung cancer, liver cancer, esophageal carcinoma, gastric cancer,intestinal cancer, renal carcinoma, oral cavity cancer, Hochkinlymphoma, pancreas cancer, colorectal cancer, cervical cancer, NonHochkin lymphoma, giiomas, melanoma, bladder carcinoma, ovarian cancer,thyroid carcinoma,

Card Posey Meat Cancer.

The invention also provides a pharmaceutical composition for cancertreatment, comprising an effective amount of micheliolide derivatives orsalt thereof of formula (II), (III), (IV), (V), in combination with apharmaceutically acceptable carrier or other anti-cancer drug.

The compounds in the embodiments of the present invention can be useddirectly or in the form of pharmaceutical composition as drug. Thepharmaceutical compositions contain 0.1-99%, preferred 0.5-90% compoundsof the present invention, and others are pharmaceutically acceptablepharmaceutical carrier and/or excipient which are harmless to animal andhuman or composition with other anti-cancer drug. Compositions in theembodiments of the present invention may be formulated as injection,tablet, and capsule.

The pharmaceutical carrier and excipient are a kind or many kinds ofsolid, semi-solid or liquid thinner and adjuvant drug. The dosage ofpharmaceutical composition of the present invention may be based on unitweight. The compounds of the invention can be administrated by injectionand oral form. The injection includes intravenous injection andintramuscular injection, and the oral form may be tablets and capsules.

Micheliolide derivatives or salt thereof in the embodiments of thepresent invention show good effect on cancer treatment, and no obviousinhibition to normal cells.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is further described in detail hereinafter withreference to the accompanying drawings as well as embodiments so as tomake the objective, technical scheme and merits thereof more apparent.

A compound, which is also micheliolide derivatives, provided in anembodiment of the present invention, is presented by the formula (I):

Wherein:

R₁ is any of H, —C(O)R₄ and —C(O)R₅R₆, wherein, R₄, R₅ and R₆ are any ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl,arylalkenyl, arylalkynyl and heterocyclic respectively;

R₃ is hydrogen, R₂ is alkyl with C₁₋₈, containing substituent or R₂═R₃is double bond;

X is any of O and R₁₀N, wherein, R₁₀ is any of hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl, arylalkenyl,arylalkynyl and heterocyclic;

Y is any of single bond, O, R₁₁N and R₁₂R₁₃C, wherein, R₁₁ is any ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl,arylalkenyl, arylalkynyl or heterocyclic;

R₁₂ and R₁₃ are any of hydrogen, fluorine, chlorine, bromine, iodine,alkyl, cycloalkyl, alkyl substituted by hydroxyl, alkenyl, alkynyl,aryl, heterocyclic, arylakyl, arylalkenyl, arylalkynyl, cyanomethyl,alkoxy or aryloxyalkyl respectively;

Herein, R₁ being H, Y being single bond, and R₂═R₃ being double bond donot exist at the same time.

In an embodiment of the present invention, the substituent of the alkylwith C₁₋₈ comprises any of cycloalkyl, heterocycloalkyl, aryl,heteroaryl.

In an embodiment of the present invention, the substituent of the alkylwith C₁₋₈ comprises amino acid fragment and pharmaceutically acceptablesalts thereof formed with inorganic and/or organic acid.

In an embodiment of the present invention, the substituent of the alkylwith C₁₋₈ comprises —NR₇R₈, and pharmaceutically acceptable saltsthereof formed with inorganic and/or organic acid;

Wherein, R₇ and R₈ are any of hydrogen, alkyl, cycloalkyl, alkylsubstituted by hydroxyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl,arylalkenyl, arylalkynyl, heterocyclic, trifluoromethyl, perfluoroalkyl,cyano, cyanomethyl, carboxyl, cabamate, sulfonyl, sulfonamide oraryloxyalkyl respectively.

In an embodiment of the present invention, the substituent of the alkylwith C₁₋₈ comprises —NR₇R₈, and pharmaceutically acceptable saltsthereof formed with inorganic and/or organic acid;

Wherein, R₇ and R₈ together with N form a ring, and R₇ and R₈ are any ofhydrogen, alkyl with 1 to 8 carbon atoms, any cycloalkyl respectively.

In an embodiment of the present invention, the ring comprises one ormore than one substituent.

In an embodiment of the present invention, the one or more than onesubstituent is any of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, alkyaryl, arylakyl, arylalkenyl, arylalkynyl and heterocyclic.

In an embodiment of the present invention, the number of the ring isthree to nine.

In an embodiment of the present invention, the substituent of the alkylwith C₁₋₈ comprises quaternary ammonium salts formed by amino acidfragment or —NR₇R₈ with R₉Z;

Wherein, Z is any of fluorine, chlorine, bromine, iodine, tosylate,methanesulfonate, benzenesulfonate, and trifluoromethanesulfonate; R9 isany of alkyl, cycloalkyl, alkyl substituted by hydroxyl, alkenyl,alkynyl, aryl, heterocyclic, arylakyl, arylalkenyl, arylalkynyl,cyanomethyl, alkoxy or aryloxyalkyl; inorganic or organic acid arehydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid,selenious acid, phosphomolybdic acid, phosphorous acid, sulfurous acid,citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid,L-lactic acid, D-lactic acid, DL-lactic acid, oxalic acid,methanesulfonic acid, valeric acid, oleic acid, lauric acid,para-toluenesulfonic acid, 1-naphthalensulfonic acid,2-naphthalensulfonic acid, phthalic acid, tartaric acid, malonic acid,succinic acid, fumaric acid, glycolic acid, thioglycolic acid, glycine,sarcocine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinicacid, benzoic acid and substituted benzoic acid.

In an embodiment of the present invention, R₂ is methylene substitutedby —NR₇R₈, wherein, where R7 and R₈ are any of hydrogen, alkyl,cycloalkyl, alkyl substituted by hydroxyl, alkenyl, alkynyl, aryl,alkyaryl, arylakyl, arylalkenyl, arylalkynyl, heterocyclic,trifluoromethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, cabamate,sulfonyl, sulfonamide or aryloxyalkyl.

In an embodiment of the present invention, R₂ is methylene substitutedby —NR₇R₈, wherein, R₇ and R₈ together with N form a ring, and R₇ and R₈are any of hydrogen, alkyl with 1 to 8 carbon atoms, any cycloalkylrespectively.

In an embodiment of the present invention, R₂ is methylene substitutedby amino acid fragment.

In an embodiment of the present invention, formula (I) is represented byformula (II)

In an embodiment of the present invention, formula (I) is represented byformula (III)

In an embodiment of the present invention, formula (I) is represented byformula (IV)

In an embodiment of the present invention, formula (I) is represented byformula (V)

In an embodiment of the present invention, the compound disclosed abovecan be used in a drug, wherein the drug is used for cancer medicaltreatment, and the cancer comprises leukemia, breast cancer, prostatecancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, livercancer, esophageal carcinoma, gastric cancer, intestinal cancer, renalcarcinoma, oral cavity cancer, Hochkin lymphoma, pancreas cancer,colorectal cancer, cervical cancer, Non Hochkin lymphoma, giiomas,melanoma, bladder carcinoma, ovarian cancer, thyroid carcinoma, CardPosey meat cancer.

In an embodiment of the present invention, the compound disclosed abovecan be in a drug, wherein the drug is used for cancer auxiliary medicaltreatment, and the cancer comprises leukemia, breast cancer, Prostatecancer, nasopharyngeal carcinoma, colorectal cancer, lung cancer, livercancer, esophageal carcinoma, gastric cancer, intestinal cancer, renalcarcinoma, oral cavity cancer, Hochkin lymphoma, pancreas cancer,colorectal cancer, cervical cancer, Non Hochkin lymphoma, giiomas,melanoma, bladder carcinoma, ovarian cancer, thyroid carcinoma, CardPosey meat cancer.

In an embodiment of the present invention, a pharmaceutical compositionis provided for cancer treatment, comprising an effective amount of acompound of claim 1, in combination with a pharmaceutically acceptablecarrier or other anti-cancer drug.

Embodiment 1

The producing of 11βH,13-Dihydro, 13-dimethylaminomicheliolide (compoundII, which is represented by formula (II))

Micheliolide (106 mg, 0.40 mmol), triethylamine (2.0 mL), Me₂NHEC1 (41mg, 0.5 mmol), and methanol (30 mL) are added to a 100-mL round flask.The resulting mixture is heated and refluxed for 3 hours, and thenconcentrated under reduced pressure to obtain crude residue which ispurified by silica gel column chromatography (petroleum ether: ethylacetate: triethylamine=50:50:0.5) to obtain 107.4 mg white solid,wherein, the yield is 86%.

Formula: C₁₇H₂₇NO₃

Molecular weight: 293

Properties: white amorphous powder

Spectra data:

¹H NMR (CDCl3, 400 MHz) δ 3.76 (t, J=10.0 Hz, 1H), 2.96 (s, 1H),2.49-2.67 (m, 3H), 2.28-2.34 (m, 1H), 2.30-2.34 (m, 2H), 2.18 (s, 6H),2.09 (br s, 2H), 1.96 (d, J=11.2 Hz, 1H) 1.67-1.73 (m, 2H), 1.60 (s,3H), 1.22 (br s, 3H), 1.18 (br s, 2H); ¹³C NMR (CDCl₃, 300 MHz) δ 177.0,131.8, 131.3, 84.0, 80.2, 58.3, 58.1, 50.9, 46.0, 44.6, 38.4, 35.3,30.0, 27.2, 23.7, 22.8.

Embodiment 2

The producing of 4-propionylmicheliolide (Compound III, which isrepresented by formula (III))

Micheliolide (106 mg, 0.40 mmol), triethylamine (2.0 mL),propionylchloride (0.2 mL) and CH₂Cl₂ (5 mL) are added to a 20-mL roundflask. The resulting mixture is stirred for 3 hour at room temperature,and then concentrated under reduced pressure, and purified by usingsilica gel column chromatography (petroleum ether: ethyl acetate=90:10),and finally 84 mg white solid are obtained. Wherein, the yield is 72%.

Formula: C₁₈H₂₄NO₄

Molecular weight: 304

Properties: white amorphous powder

Spectra data:

¹H NMR (CDCl₃, 400 MHz) δ 6.14 (s, 1H), 5.42 (s, 1H), 3.74 (t, J=10.0Hz, 1H), 1.80-2.74 (m, 12H), 1.67 (s, 3H), 1.50 (s, 3H), 1.07 (t, J=4.0Hz, 3H); ¹³C NMR (CDCl₃, 300 MHz) δ 173.8, 170.1, 139.5, 131.5, 130.4,118.6, 88.4, 83.0, 56.6, 50.1, 36.5, 34.9, 30.4, 28.7, 25.9, 24.1, 18.8,9.1.

Embodiment 3

The producing of 1,10-Epoxymicheliolide (Compound IV, its structure wasrepresented by formula (IV))

Micheliolide (106 mg, 0.40 mmol), m-CPBA (2.0 mL), and CH₂Cl₂ (5 mL) areadded to a 20-mL round flask. The resulting mixture is stirred for 6hours at the room temperature, and then concentrated under reducedpressure, purified by using silica gel column chromatography (petroleumether:ethyl acetate=80:20), and finally 96 mg white solid are obtained.Wherein, the yield is 91%.

Formula: C₁₅H₂₀NO₄

Molecular weight: 264

Properties: white amorphous powder

Spectra data:

¹H NMR (CDCl₃, 400 MHz) δ 6.13 (t, J=3.2 Hz, 1H), 5.44 (d, J=2.8 Hz,1H), 3.73 (t, J=10.4 Hz, 1H), 1.30-2.46 (m, 11H), 1.29 (s, 3H), 1.28 (s,3H); ¹³C NMR (CDCl₃, 300 MHz) δ 168.7, 137.8, 118.6, 79.2, 77.3, 74.2,66.7, 52.6, 48.4, 37.1, 33.8, 29.0, 24.6, 22.5, 21.3.

Embodiment 4

The producing of 11βH,13-Dihydro, 13-dimethylaminomicheliolidehydrochloride (Compound V, its structure was represented by formula (V))

compound II (293 mg, 1 mmol) is dissolved in CH₂Cl₂ (2 mL) and wasStirred at room temperature, hydrochloric acid is added until pH=4-5.The mixture was extracted with CH₂Cl₂ (2×10 mL). The aqueous layer islyophilized to obtain white solid, wherein, the yield is 82%. Thestructure data of the produced 11S, 11,13-Dihydro,13-dimethylaminomicheliolide hydrochloride are as follows:

Formula: C₁₇H₂₈ClNO₃

Molecular weight: 328.5

Properties: White amorphous powder

Spectra data:

[α]_(D) ²⁰=−42.0 (c=10, H₂O); IR (KBr): 3334, 2927, 2856, 1767, 1467,992, 967, 874, 831, 719, 669, 626, 504 cm⁻¹; ¹H NMR (D₂O, 400 MHz) δ4.14 (t, J=10.3 Hz, 1H), 3.51 (q, J=12.6 Hz, 1H), 3.40 (dd, J=13.3, 2.9Hz, 1H), 3.18-3.04 (m, 1H), 2.96 (d, J=10.6 Hz, 6H), 2.67 (d, J=10.2 Hz,1H), 2.37 (dd, J=16.2, 8.1 Hz, 1H), 2.27-2.05 (m, 4H), 1.87 (d, J=12.9Hz, 1H), 1.73 (dd, J=19.5, 11.7 Hz, 2H), 1.66 (s, 3H), 1.46-1.31 (m,2H), 1.26 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 178.4, 132.6, 131.4, 85.1,80.7, 56.9, 55.6, 49.9, 45.1, 42.3, 41.5, 39.2, 34.4, 29.5, 25.9, 23.2,21.4.

Embodiment 5 The Pharmacological of Micheliolide Derivatives

A variety of cancer cells are suspended to 2×10⁵/mL, and then added into24-hole Round-bottomed tissue culture plate. After that micheliolide andits derivatives are added, herein a test with one density occupies 5holes. The resulting suspension are incubated (under 37° C., 5% CO₂) for18 hours to allow the compounds to take effect. A absorbance (A) valueis measured by using the method of MTT assay and an enzyme-linkeddetector under 570 nm wavelength, and then the inhibitory activity ofthe compounds is concluded. The result of the inhibitory activity isshown in Table 1.

TABLE 1 The inhibitory activity of micheliolide and its derivativesagainst different cancer cells (IC₅₀, nM) Compound Compound CompoundCompound Cell lines II III IV V HL-60 2.4 4.5 5.8 11.5 K562 4.2 6.7 9.721.4 MCF-7 4.6 3.4 8.9 26.8 CNE-1 11.2 5.9 6.7 22.5 CNE-2 16.5 12.4 5.616.9 SW620 5.8 5.6 3.8 13.5 A549 7.2 7.7 5.7 18.1 HepG-2 4.5 15.4 7.427.9 Ec9706 9.2 7.6 6.6 15.7 SGC7901 14.6 14.7 13.4 24.9 SW1116 11.521.5 11.7 31.2 A498 12.4 5.3 4.3 16.3 ASPC-1 3.9 15.1 26.4 33.6 HT-294.8 9.8 9.8 19.2 HeLa 9.4 17.3 9.7 33.4 GL15 12.6 14.3 21.5 25.8 B16F13.4 13.2 5.2 18.6 T24 14.2 13.6 7.9 22.5 SKOV3 5.9 9.4 10.4 15.4 SW57917.3 22.5 12.4 32.6 PC-3 8.7 11.4 17.2 23.5

In Table 1, HL-60, K562, MCF-7, CNE-1, CNE-2, SW620, A549, HepG2,Ec9706, SGC7901, SW1116, A498, ASPC-1, HT-29, HeLa, GE1S, B16F1, T24,SKOV3, SW579, PC-3, represents acute leukemia cell lines, Chronicleukemia cell lines, Breast cancer cell lines, High differentiationnasopharyngeal carcinoma cell line, Poorly differentiated nasopharyngealcarcinoma cell lines, Colorectal cancer cell line, Lung cancer celllines, Hepatocellular carcinoma cell lines, Esophageal cancer cell line,Gastric cancer cell line, Colon cancer cell line, Renal cell carcinomacell line, Pancreatic cancer cell line, Colon cancer cell lines, uterinecervical cancer cell lines, Horny man neuroblastoma cell lines, Melanomacell line, human bladder cancer cell line, ovarian cancer cell lines,thyroid cancer cells, prostate cancer cell lines, respectively.

The tested result shows the compounds show strong inhibitory activityagainst the tested cells, however, have no obvious inhibition againstnormal cells at 50 μM. Embodiment 6 Injection

Compounds II, III, IV, V produced in the embodiments 1 to 4, isrespectively dissolved in a small amount of DMSO. Injective water isthen added into the mixed solvent and filtered finely, after potting andsterilization, finally the injection is obtained.

Embodiment 7 Tablet

The compounds II, III, IV, V produced in the embodiments 1 to 4, ismixed respectively with excipients according to weight ratio of 5:1, andthen tableted to obtain tablets.

Embodiment 8 Capsule

he compounds II, III, IV, V prepared in the Examples 1-4, is mixedrespectively with excipients according to weight ratio of 5:1 to obtaincapsules.

The compounds, usage and producing methods of the present invention havebeen described with specific embodiments. It is obviously for thoseskilled in the art to appropriately change raw materials, processconditions et al, to achieve corresponding purposes. The changes arestill in the scope of the present invention. Any modification,equivalent replacement and improvement made without departing from thespirit and principle of the present invention should be included withinthe protection scope thereof.

1. A compound of the formula (I):

Wherein: R₁ is any of H, —C(O)R₄ and —C(O)R₅R₆, wherein, R₄, R₅ and R₆are any of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,alkyaryl, arylakyl, arylalkenyl, arylalkynyl and heterocyclicrespectively; R₃ is hydrogen, R₂ is alkyl with C₁₋₈, containingsubstituent or R₂═R₃ is double bond; X is any of O and R₁₀N, wherein,R₁₀ is any of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,alkyaryl, arylakyl, arylalkenyl, arylalkynyl and heterocyclic; Y is anyof single bond, O, R₁₁N and R₁₂R₁₃C, wherein, R₁₁ is any of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl,arylalkenyl, arylalkynyl or heterocyclic; R₁₂ and R₁₃ are any ofhydrogen, fluorine, chlorine, bromine, iodine, alkyl, cycloalkyl, alkylsubstituted by hydroxyl, alkenyl, alkynyl, aryl, heterocyclic, arylakyl,arylalkenyl, arylalkynyl, cyanomethyl, alkoxy or aryloxyalkylrespectively; Herein, R₁ being H, Y being single bond, and R₂═R₃ beingdouble bond do not exist at the same time.
 2. A compound of claim 1,wherein, the substituent of the alkyl with C₁₋₈ comprises any ofcycloalkyl, heterocycloalkyl, aryl, heteroaryl.
 3. A compound of claim1, wherein, the substituent of the alkyl with C₁₋₈ comprises amino acidfragment and pharmaceutically acceptable salts thereof formed withinorganic and/or organic acid.
 4. A compound of claim 1, wherein, thesubstituent of the alkyl with C₁₋₈ comprises —NR₇R₈, andpharmaceutically acceptable salts thereof formed with inorganic and/ororganic acid; Wherein, R₇ and R₈ are any of hydrogen, alkyl, cycloalkyl,alkyl substituted by hydroxyl, alkenyl, alkynyl, aryl, alkyaryl,arylakyl, arylalkenyl, arylalkynyl, heterocyclic, trifluoromethyl,perfluoroalkyl, cyano, cyanomethyl, carboxyl, cabamate, sulfonyl,sulfonamide or aryloxyalkyl respectively.
 5. A compound of claim 1,wherein, the substituent of the alkyl with C₁₋₈ comprises —NR₇R₈, andpharmaceutically acceptable salts thereof formed with inorganic and/ororganic acid; Wherein, R₇ and R₈ together with N form a ring, and R₇ andR₈ are any of hydrogen, alkyl with 1 to 8 carbon atoms, any cycloalkylrespectively.
 6. A compound of claim 5, wherein, the ring comprises oneor more than one substituent.
 7. A compound of claim 6, wherein, the oneor more than one substituent is any of hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, alkyaryl, arylakyl, arylalkenyl, arylalkynyl andheterocyclic.
 8. A compound of claim 5, wherein, the number of the ringis three to nine.
 9. A compound of claim 1, wherein, the substituent ofthe alkyl with C₁ comprises quaternary ammonium salts formed by aminoacid fragment or —NR₇R₈ with R₉Z; Wherein, Z is any of fluorine,chlorine, bromine, iodine, tosylate, methanesulfonate, benzenesulfonate,and trifluoromethanesulfonate; R9 is any of alkyl, cycloalkyl, alkylsubstituted by hydroxyl, alkenyl, alkynyl, aryl, heterocyclic, arylakyl,arylalkenyl, arylalkynyl, cyanomethyl, alkoxy or aryloxyalkyl; inorganicor organic acid are hydrofluoric acid, hydrochloric acid, hydrobromicacid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid,carbonic acid, boric acid, selenious acid, phosphomolybdic acid,phosphorous acid, sulfurous acid, citric acid, maleic acid, D-malicacid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid,DL-lactic acid, oxalic acid, methanesulfonic acid, valeric acid, oleicacid, lauric acid, para-toluenesulfonic acid, 1-naphthalensulfonic acid,2-naphthalensulfonic acid, phthalic acid, tartaric acid, malonic acid,succinic acid, fumaric acid, glycolic acid, thioglycolic acid, glycine,sarcocine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinicacid, benzoic acid and substituted benzoic acid.
 10. A compoundaccording to claim 1, wherein R₂ is methylene substituted by —NR₇R₈,wherein, where R7 and R₈ are any of hydrogen, alkyl, cycloalkyl, alkylsubstituted by hydroxyl, alkenyl, alkynyl, aryl, alkyaryl, arylakyl,arylalkenyl, arylalkynyl, heterocyclic, trifluoromethyl, perfluoroalkyl,cyano, cyanomethyl, carboxyl, cabamate, sulfonyl, sulfonamide oraryloxyalkyl.
 11. A compound according to claim 1, wherein R₂ ismethylene substituted by —NR₇R₈, wherein, R₇ and R₈ together with N forma ring, and R₇ and R₈ are any of hydrogen, alkyl with 1 to 8 carbonatoms, any cycloalkyl respectively.
 12. A compound according to claim 1,wherein R₂ is methylene substituted by amino acid fragment.
 13. Acompound according to claim 1, wherein, formula (I) is represented byformula (II)


14. A compound according to claim 1, wherein, formula (I) is representedby formula (III)


15. A compound according to claim 1, wherein, formula (I) is representedby formula (IV)


16. A compound according to claim 1, wherein, formula (I) is representedby formula (V)


17. The usage of a compound of claim 1 in a drug, wherein the drug isused for cancer medical treatment, and the cancer comprises leukemia,breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectalcancer, lung cancer, liver cancer, esophageal carcinoma, gastric cancer,intestinal cancer, renal carcinoma, oral cavity cancer, Hochkinlymphoma, pancreas cancer, colorectal cancer, cervical cancer, NonHochkin lymphoma, giiomas, melanoma, bladder carcinoma, ovarian cancer,thyroid carcinoma, Card Posey meat cancer.
 18. A pharmaceuticalcomposition for cancer treatment, comprising an effective amount of acompound of claim 1, in combination with a pharmaceutically acceptablecarrier or other anti-cancer drug.